Injury, repair and/or chronic proliferation of pulmonary epithelial cells may govern the development of a lung of lung diseases including pulmonary fibrosis. Inhalation of the fibrogenic minerals, silica and asbestos, which induce oxidative stress, cause apoptosis, a programmed type of cell death. Apoptosis and other phenotypic responses are regulated in many cell types by Mitogen-Activated Protein Kinases (MAPK), i.e. the Extracellular Signal-Regulated Kinases (ERKs), c-Jun-N-terminal kinases (JNK) and p38 cascades. Hypothesis #1 to be tested here is that sustained activation of the ERK, as opposed to the JNK-p38 kinases, is critical to the development of apoptosis by asbestos and silica in vitro. A second hypothesis to be tested is that ERK kinase activation and apoptosis play a role in epithelial cell repair, and is an important defence mechanism in the development of pulmonary fibrosis. To test Hypothesis #1, the patterns and kinetics of ERK, JNK and p38 kinase activation first will be correlated over time with the development of apoptosis by agents selectively inducing these phenotypic endpoints in rat alveolar type II epithelial (RLE) cells and human small airway epithelial cells (SAEC) (Specific Aim #1). To determine whether activation of ERKs is casually related to the development of apoptosis, selective inhibitors of ERKs and JNK/p38 kinases and transfection of RLE cells with dominant negative forms of ERKs will be used to determine if asbestos or silica-induced apoptosis is significantly ameliorated (Specific Aim #2). To test Hypothesis #2, transgenic mice over-expressing dominant negative forms of MEK-1 (ERK kinase) via lung epithelial cell-specific promoters will be exposed in inhalation experiments to silica or asbestos and characterized, using quantitative markers for the development of apoptosis, cell proliferation, and pulmonary fibrosis, to determine if the severity and extent of disease are altered (Specific Aim #3). Results will indicate not only whether apoptosis is a protective repair mechanism in pulmonary fibrosis, but also will provide a rationale for modification of ell signalling pathways governing apoptosis in the treatment of fibrotic lung disease.